: Cancers of the skin account for nearly half of human malignancies and result in considerable costs and morbidity. Their incidence is dramatically increased in organ transplant recipients (OTRs). A subset of OTRs develops multiple skin cancer, especially squamous cell carcinoma (SCC), several years after transplantation, representing a significant clinical problem. The cause of the about 70-fold increase in SCC incidence in OTRs is currently unclear. We will perform a comprehensive genome-wide search using array CGH and polymorphic markers to detect DNA copy number aberrations and allelic imbalance, as well as sequencing P53, in order to detect somatic genetic events in SCCs arising in OTRs and immunocompetent individuals (non-OTRs). We will also determine the progression of somatic events by analyzing invasive tumors that have adjacent precursor stages such as SCC in situ and actinic keratoses. Aberrations in these two groups will be compared in order to determine if they provide an indication on the mechanism by which anti-rejection treatment facilitates SCCs development. Candidate mechanisms include human papilloma virus, direct action of anti-rejection drugs (ARDs), or indirect action of ARDs through reduced immunosurveillance. We will also localize and identify novel candidate genes involved in SCC development. Our first priority will be to identify human cancer susceptibility genes that are relevant in for SCC in OTRs, and possibly SCC in general. We will do this by determining if there are regions of recurrent abnormality in multiple tumors within individual OTRs, and if a common allele is preferentially gained or lost within each patient. If such a region is found, that will indicate the likely presence of a polymorphic gene in the region that affects SCC susceptibility. Highresolution SNP-analysis will then be used to identify haplotypes in the region that are shared among highly susceptible individuals and that occur infrequently in matched OTRs that are relatively resistant to SCC development. The shared haplotypes will be used as a lead to identify the causative polymorphisms.Because the risk factors for SCC are highly similar between OTRs and the general population, susceptibility genes identified may be of general relevance for the disease. If no indication of a susceptibility locus is found in the OTRs with multiple tumors, we will apply more conventional positional cloning techniques to identify genes within the aberrations that contribute to SCC development.